tbuckley/cabot-search huggingface dataset:
Dapagliflozin‐Loaded Exosome Mimetics Facilitate Diabetic Wound Healing by HIF‐1<i>α</i>‐Mediated Enhancement of Angiogenesis
Authors: Weiyue Zhang, Lutong Wang, Haoyu Guo, Lulu Chen, Xin Huang
Journal: Advanced Healthcare Materials (2022)

Angiogenesis plays a critical role in diabetic wound healing. However, no effective strategies have been developed to target endothelial cells (ECs) to facilitate diabetic wound healing. Dapagliflozin (DA) as a sodium-glucose linked transporter 2 (SGLT2) inhibitor, may promote neovascularization in diabetic mice via HIF-1α-mediated enhancement of angiogenesis. Here, the bioinspired nanovesicles (NVs) prepared from induced pluripotent stem cells-derived ECs through an extrusion approach are reported, which can function as exosome mimetics to achieve targeted deliver of DA. Abundant membrane C-X-C motif chemokine receptor 4 conferred the EC-targeting ability of these NVs and the endothelial homology facilitated the accumulation in ECs. Furthermore, these DA-loaded induced pluripotent stem cells (iPSC)-EC NVs can facilitate angiogenesis and diabetic wound healing by HIF-1α/VEGFA pathway. Taken together, this study indicated that targeting ECs and regulating angiogenesis may be a promising strategy for the treatment of diabetic wound healing.
CXCL12/CXCR4: An amazing challenge and opportunity in the fight against fibrosis
Authors: Xue Wu, Lu Qian, Huadong Zhao, Wangrui Lei, Yanqing Liu, Xiaoling Xu, Jiawen Li, Zhi Yang, Du Wang, Yuchen Zhang, Yan Zhang, Ran Tang, Yang Yang, Ye Tian
Journal: Ageing Research Reviews (2022)
Bortezomib, Bendamustine and Dexamethasone vs Thalidomide, Bendamustine and Dexamethasone in Myeloma patients presenting with renal failure (OPTIMAL): a randomised, multi-centre phase II trial
Authors: Karthik Ramasamy, Gulnaz Iqbal, Richard Brouwer, Victoria Stalker, Salma Akhtar, Sherin Varghese, Jindriska Lindsay, Stephen Schey, Mark Drayson, Janet Dunn
Journal: Blood Cancer Journal (2022)
NLRP3 Inflammasome Activation Through Heart-Brain Interaction Initiates Cardiac Inflammation and Hypertrophy During Pressure Overload
Authors: Yasutomi Higashikuni, Wenhao Liu, Genri Numata, Kimie Tanaka, Daiju Fukuda, Yu Tanaka, Yoichiro Hirata, Teruhiko Imamura, Eiki Takimoto, Issei Komuro, Masataka Sata
Journal: Circulation (2022)

Mechanical stress on the heart, such as high blood pressure, initiates inflammation and causes hypertrophic heart disease. However, the regulatory mechanism of inflammation and its role in the stressed heart remain unclear. IL-1β (interleukin-1β) is a proinflammatory cytokine that causes cardiac hypertrophy and heart failure. Here, we show that neural signals activate the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3) inflammasome for IL-1β production to induce adaptive hypertrophy in the stressed heart.C57BL/6 mice, knockout mouse strains for NLRP3 and P2RX7 (P2X purinoceptor 7), and adrenergic neuron-specific knockout mice for SLC17A9, a secretory vesicle protein responsible for the storage and release of ATP, were used for analysis. Pressure overload was induced by transverse aortic constriction. Various animal models were used, including pharmacological treatment with apyrase, lipopolysaccharide, 2'(3')-O-(4-benzoylbenzoyl)-ATP, MCC950, anti-IL-1β antibodies, clonidine, pseudoephedrine, isoproterenol, and bisoprolol, left stellate ganglionectomy, and ablation of cardiac afferent nerves with capsaicin. Cardiac function and morphology, gene expression, myocardial IL-1β and caspase-1 activity, and extracellular ATP level were assessed. In vitro experiments were performed using primary cardiomyocytes and fibroblasts from rat neonates and human microvascular endothelial cell line. Cell surface area and proliferation were assessed.Genetic disruption of NLRP3 resulted in significant loss of IL-1β production, cardiac hypertrophy, and contractile function during pressure overload. A bone marrow transplantation experiment revealed an essential role of NLRP3 in cardiac nonimmune cells in myocardial IL-1β production and cardiac phenotype. Pharmacological depletion of extracellular ATP or genetic disruption of the P2X7 receptor suppressed myocardial NLRP3 inflammasome activity during pressure overload, indicating an important role of ATP/P2X7 axis in cardiac inflammation and hypertrophy. Extracellular ATP induced hypertrophic changes of cardiac cells in an NLRP3- and IL-1β-dependent manner in vitro. Manipulation of the sympathetic nervous system suggested sympathetic efferent nerves as the main source of extracellular ATP. Depletion of ATP release from sympathetic efferent nerves, ablation of cardiac afferent nerves, or a lipophilic β-blocker reduced cardiac extracellular ATP level, and inhibited NLRP3 inflammasome activation, IL-1β production, and adaptive cardiac hypertrophy during pressure overload.Cardiac inflammation and hypertrophy are regulated by heart-brain interaction. Controlling neural signals might be important for the treatment of hypertensive heart disease.
Lipoprotein(a) in Youth and Prediction of Major Cardiovascular Outcomes in Adulthood
Authors: Olli Raitakari, Noora Kartiosuo, Katja Pahkala, Nina Hutri-Kähönen, Lydia A. Bazzano, Wei Chen, Elaine M. Urbina, David R. Jacobs, Alan Sinaiko, Julia Steinberger, Trudy Burns, Stephen R. Daniels, Alison Venn, Jessica G. Woo, Terry Dwyer, Markus Juonala, Jorma Viikari
Journal: Circulation (2022)

Background: Elevated lipoprotein(a) [Lp(a)] is a common risk factor for cardiovascular disease outcomes with unknown mechanisms. We examined its potential role in identifying youths who are at increased risk of developing adult atherosclerotic cardiovascular disease (ASCVD). Methods: Lp(a) levels measured in youth 9 to 24 years of age were linked to adult ASCVD and carotid intima-media thickness in the YFS (Cardiovascular Risk in Young Finns Study), in which 95 of the original 3596 participants (2.7%) recruited as children have been diagnosed with ASCVD at a median of 47 years of age. Results observed in YFS were replicated with the use of data for White participants from the BHS (Bogalusa Heart Study). In BHS, 587 White individuals had data on youth Lp(a) (measured at 8–17 years of age) and information on adult events, including 15 cases and 572 noncases. Analyses were performed with the use of Cox proportional hazard regression. Results: In YFS, those who had been exposed to high Lp(a) level in youth [defined as Lp(a) ≥30 mg/dL] had ≈2 times greater risk of developing adult ASCVD compared with nonexposed individuals (hazard ratio, 2.0 [95% CI, 1.4–2.6]). Youth risk factors, including Lp(a), low-density lipoprotein cholesterol, body mass index, and smoking, were all independently associated with higher risk. In BHS, in an age- and sex-adjusted model, White individuals who had been exposed to high Lp(a) had 2.5 times greater risk (95% CI, 0.9–6.8) of developing adult ASCVD compared with nonexposed individuals. When also adjusted for low-density lipoprotein cholesterol and body mass index, the risk associated with high Lp(a) remained unchanged (hazard ratio, 2.4 [95% CI, 0.8–7.3]). In a multivariable model for pooled data, individuals exposed to high Lp(a) had 2.0 times greater risk (95% CI, 1.0–3.7) of developing adult ASCVD compared with nonexposed individuals. No association was detected between youth Lp(a) and adult carotid artery thickness in either cohort or pooled data. Conclusions: Elevated Lp(a) level identified in youth is a risk factor for adult atherosclerotic cardiovascular outcomes but not for increased carotid intima-media thickness.
IL-6/STAT3 signaling in tumor cells restricts the expression of frameshift-derived neoantigens by SMG1 induction
Authors: Daniel Meraviglia-Crivelli, Helena Villanueva, Angelina Zheleva, María Villalba-Esparza, Beatriz Moreno, Ashwathi Puravankara Menon, Alfonso Calvo, Javier Cebollero, Martin Barainka, Igor Ruiz de los Mozos, Carlos Huesa-Berral, Fernando Pastor
Journal: Molecular Cancer (2022)

Abstract Background The quality and quantity of tumor neoantigens derived from tumor mutations determines the fate of the immune response in cancer. Frameshift mutations elicit better tumor neoantigens, especially when they are not targeted by nonsense-mediated mRNA decay (NMD). For tumor progression, malignant cells need to counteract the immune response including the silencing of immunodominant neoantigens (antigen immunoediting) and promoting an immunosuppressive tumor microenvironment. Although NMD inhibition has been reported to induce tumor immunity and increase the expression of cryptic neoantigens, the possibility that NMD activity could be modulated by immune forces operating in the tumor microenvironment as a new immunoediting mechanism has not been addressed. Methods We study the effect of SMG1 expression (main kinase that initiates NMD) in the survival and the nature of the tumor immune infiltration using TCGA RNAseq and scRNAseq datasets of breast, lung and pancreatic cancer. Different murine tumor models were used to corroborate the antitumor immune dependencies of NMD. We evaluate whether changes of SMG1 expression in malignant cells impact the immune response elicited by cancer immunotherapy. To determine how NMD fluctuates in malignant cells we generated a luciferase reporter system to track NMD activity in vivo under different immune conditions. Cytokine screening, in silico studies and functional assays were conducted to determine the regulation of SMG1 via IL-6/STAT3 signaling. Results IL-6/STAT3 signaling induces SMG1, which limits the expression of potent frameshift neoantigens that are under NMD control compromising the outcome of the immune response. Conclusion We revealed a new neoantigen immunoediting mechanism regulated by immune forces (IL-6/STAT3 signaling) responsible for silencing otherwise potent frameshift mutation-derived neoantigens.
Identification of common and distinct origins of human serum and breastmilk IgA1 by mass spectrometry-based clonal profiling
Authors: Kelly A. Dingess, Max Hoek, Danique M. H. van Rijswijk, Sem Tamara, Maurits A. den Boer, Tim Veth, Mirjam J. A. Damen, Arjan Barendregt, Michelle Romijn, Hannah G. Juncker, Britt J. van Keulen, Gestur Vidarsson, Johannes B. van Goudoever, Albert Bondt, Albert J. R. Heck
Journal: Cellular and Molecular Immunology (2022)

Abstract The most abundant immunoglobulin present in the human body is IgA. It has the highest concentrations at the mucosal lining and in biofluids such as milk and is the second most abundant class of antibodies in serum. We assessed the structural diversity and clonal repertoire of IgA1-containing molecular assemblies longitudinally in human serum and milk from three donors using a mass spectrometry-based approach. IgA-containing molecules purified from serum or milk were assessed by the release and subsequent analysis of their Fab fragments. Our data revealed that serum IgA1 consists of two distinct structural populations, namely monomeric IgA1 (∼80%) and dimeric joining (J-) chain coupled IgA1 (∼20%). Also, we confirmed that IgA1 in milk is present solely as secretory (S)IgA, consisting of two (∼50%), three (∼33%) or four (∼17%) IgA1 molecules assembled with a J-chain and secretory component (SC). Interestingly, the serum and milk IgA1-Fab repertoires were distinct between monomeric, and J-chain coupled dimeric IgA1. The serum dimeric J-chain coupled IgA1 repertoire contained several abundant clones also observed in the milk IgA1 repertoire. The latter repertoire had little to no overlap with the serum monomeric IgA1 repertoire. This suggests that human IgA1s have (at least) two distinct origins; one of these produces dimeric J-chain coupled IgA1 molecules, shared in human serum and milk, and another produces monomeric IgA1 ending up exclusively in serum.
Epsin Nanotherapy Regulates Cholesterol Transport to Fortify Atheroma Regression
Authors: Kui Cui, Xinlei Gao, Beibei Wang, Hao Wu, Kulandaisamy Arulsamy, Yunzhou Dong, Yuling Xiao, Xingya Jiang, Marina V. Malovichko, Kathryn Li, Qianman Peng, Yao Wei Lu, Bo Zhu, Rongbin Zheng, Scott Wong, Douglas B. Cowan, MacRae Linton, Sanjay Srivastava, Jinjun Shi, Kaifu Chen, Hong Chen
Journal: Circulation Research (2022)

Excess cholesterol accumulation in lesional macrophages elicits complex responses in atherosclerosis. Epsins, a family of endocytic adaptors, fuel the progression of atherosclerosis; however, the underlying mechanism and therapeutic potential of targeting Epsins remains unknown. In this study, we determined the role of Epsins in macrophage-mediated metabolic regulation. We then developed an innovative method to therapeutically target macrophage Epsins with specially designed S2P-conjugated lipid nanoparticles, which encapsulate small-interfering RNAs to suppress Epsins.
Association of location of BRCA1 and BRCA2 mutations with benefit from olaparib and bevacizumab maintenance in high-grade ovarian cancer: phase III PAOLA-1/ENGOT-ov25 trial subgroup exploratory analysis
Authors: S.I. Labidi-Galy, M. Rodrigues, J.L. Sandoval, J.E. Kurtz, F. Heitz, A.M. Mosconi, I. Romero, U. Denison, S. Nagao, I. Vergote, G. Parma, T.J. Nøttrup, E. Rouleau, G. Garnier, A. El-Balat, C. Zamagni, C. Martín-Lorente, E. Pujade-Lauraine, A. Fiévet, I.L. Ray-Coquard
Journal: Annals of Oncology (2022)

Background: In the phase III PAOLA-1 study, the addition of maintenance olaparib to bevacizumab in patients with newly diagnosed high-grade ovarian cancer (HGOC) resulted in prolonged progression-free survival (PFS), particularly for homologous recombination deficiency-positive tumors, including those with a BRCA mutation (BRCAm).The magnitude of benefit from olaparib and bevacizumab according to the location of mutation in BRCA1/BRCA2 remains to be explored.Patients and methods: Patients with advanced-stage HGOC responding after platinum-based chemotherapy þ bevacizumab received maintenance therapy bevacizumab (15 mg/kg q3w for 15 months) þ either olaparib (300 mg b.i.d. for 24 months) or placebo.PFS was analyzed in the subgroup of patients with BRCA1m/BRCA2m according to mutation location in the functional domains of BRCA1 [Really Interesting Gene (RING), DNA-binding domain (DBD), or C-terminal domain of BRCA1 (BRCT)] and BRCA2 [RAD51-binding domain (RAD51-BD); DBD].Results: From 806 randomized patients, 159 harbored BRCA1m (19.7%) and 74 BRCA2m (9.2%).BRCA1m in RING, DBD, and BRCT domains was detected in 18, 40, and 33 patients, and BRCA2m in RAD51-BD and DBD in 36 and 13 patients, respectively.After a median follow-up of 25.5 months, benefit from maintenance olaparib þ bevacizumab was observed irrespective of location of BRCAm.The benefit was particularly high for those with BRCA1m located in the DBD, with 24-month PFS estimated to be 89% and 15% [olaparib þ bevacizumab versus placebo þ bevacizumab hazard ratio ¼ 0.08 (95% confidence interval 0.02-0.28);interaction P ¼ 0.03].In BRCA2m patients, 24-month PFS rates for those with mutations located in the DBD were 90% and 100% (olaparib þ bevacizumab versus placebo þ bevacizumab), respectively.Conclusions: Advanced-stage BRCA-mutated HGOC patients reported PFS benefit from maintenance olaparib and bevacizumab regardless of mutation location.The benefit is particularly high for patients with mutations located in the DBD of BRCA1.Mutations located in the DBD of BRCA2 are also associated with excellent outcome.
Cross-regulome profiling of RNA polymerases highlights the regulatory role of polymerase III on mRNA transcription by maintaining local chromatin architecture
Authors: Yongpeng Jiang, Jie Huang, Kai Tian, Xiao Yi, Haonan Zheng, Yi Zhu, Tiannan Guo, Xiong Ji
Journal: Genome biology (2022)

Abstract Background Mammalian cells have three types of RNA polymerases (Pols), Pol I, II, and III. However, the extent to which these polymerases are cross-regulated and the underlying mechanisms remain unclear. Results We employ genome-wide profiling after acute depletion of Pol I, Pol II, or Pol III to assess cross-regulatory effects between these Pols. We find that these enzymes mainly affect the transcription of their own target genes, while certain genes are transcribed by the other polymerases. Importantly, the most active type of crosstalk is exemplified by the fact that Pol III depletion affects Pol II transcription. Pol II genes with transcription changes upon Pol III depletion are enriched in diverse cellular functions, and Pol III binding sites are found near their promoters. However, these Pol III binding sites do not correspond to transfer RNAs. Moreover, we demonstrate that Pol III regulates Pol II transcription and chromatin binding of the facilitates chromatin transcription (FACT) complex to alter local chromatin structures, which in turn affects the Pol II transcription rate. Conclusions Our results support a model suggesting that RNA polymerases show cross-regulatory effects: Pol III affects local chromatin structures and the FACT-Pol II axis to regulate the Pol II transcription rate at certain gene loci. This study provides a new perspective for understanding the dysregulation of Pol III in various tissues affected by developmental diseases.
Real-time and label-free biosensing using moiré pattern generated by bioresponsive hydrogel
Authors: Semin Kim, Geehong Kim, Yong Woo Ji, Chae-Eun Moon, Yuna Jung, Hyung Keun Lee, JaeJong Lee, Won-Gun Koh
Journal: Bioactive Materials (2022)

Bioresponsive hydrogels are smart materials that respond to various external stimuli and exhibit great potential as biosensors owing to their capability of real-time and label-free detection. Here, we propose a sensing platform based on bioresponsive hydrogels, employing the concept of moiré patterns. Two sets of line patterns with different pitch sizes are prepared; a hydrogel grating whose pitch size changes according to external stimuli and a reference grating with constant pitch size. The volume changes of the hydrogel caused by external stimuli changes the pitch size of the hydrogel grating, and subsequently, the pitch sizes of the moiré patterns (moiré signal), whose values can be obtained in a real-time and label-free manner through customized moiré microscopy and signal processing. After confirming that the pH-induced swelling of hydrogel could be monitored using moiré patterns, we performed moiré pattern-based detection of specific proteins using protein-responsive hydrogel that underwent shrinking via interaction with target proteins. Brain-derived neurotrophic factor and platelet-derived growth factor were selected as the model proteins, and our proposed system successfully detected both proteins at nanomolar levels. In both cases, the pitch size change of hydrogel grating was monitored much more sensitively using moiré patterns than through direct measurements. The changes in the moiré signals caused by target proteins were detected in ex-vivo environments using a custom-made intraocular lens incorporating the hydrogel grating, demonstrating the capability of the proposed system to detect various markers in intraocular aqueous humor, when implanted in the eye.
Neutrophil extracellular traps have auto-catabolic activity and produce mononucleosome-associated circulating DNA
Authors: Ekaterina Pisareva, Lucia Mihalovičová, Brice Pastor, Andrei Kudriavtsev, Alexia Mirandola, Thibault Mazard, Stephanie Badiou, Ulrich Maus, Lena Ostermann, Julia Weinmann-Menke, Elmo W. I. Neuberger, Perikles Simon, Alain R. Thierry
Journal: Genome Medicine (2022)

As circulating DNA (cirDNA) is mainly detected as mononucleosome-associated circulating DNA (mono-N cirDNA) in blood, apoptosis has until now been considered as the main source of cirDNA. The mechanism of cirDNA release into the circulation, however, is still not fully understood. This work addresses that knowledge gap, working from the postulate that neutrophil extracellular traps (NET) may be a source of cirDNA, and by investigating whether NET may directly produce mono-N cirDNA.
Socioeconomic inequalities in cancer mortality between and within countries in Europe: a population-based study
Authors: Salvatore Vaccarella, Damien Georges, Freddie Bray, Ophira Ginsburg, Hadrien Charvat, Pekka Martikainen, Henrik Brønnum-Hansen, Patrick Deboosere, Matthias Bopp, Mall Leinsalu, Barbara Artnik, Valentina Lorenzoni, Esther De Vries, Michael Marmot, Paolo Vineis, Johan Mackenbach, Wilma Nusselder
Journal: The Lancet Regional Health - Europe (2022)

Reducing socioeconomic inequalities in cancer is a priority for the public health agenda. A systematic assessment and benchmarking of socioeconomic inequalities in cancer across many countries and over time in Europe is not yet available.
Corrigendum to “Bioinspired supramolecular nanofiber hydrogel through self-assembly of biphenyl-tripeptide for tissue engineering” [Bioact. Mater. 8 (2022) 396–408]
Authors: Yong Sun, Xing Li, Mingda Zhao, Yafang Chen, Yang Xu, Kefeng Wang, Shaoquan Bian, Qing Jiang, Yujiang Fan, Xingdong Zhang
Journal: Bioactive Materials (2022)

[This corrects the article DOI: 10.1016/j.bioactmat.2021.05.054.].
<scp>IgG</scp> memory B cells expressing <i>IL4R</i> and <i>FCER2</i> are associated with atopic diseases
Authors: Carlos J. Aranda, Edgar Gonzalez‐Kozlova, Sean P. Saunders, Weslley Fernandes‐Braga, Miyo Ota, Sriram Narayanan, Jin‐Shu He, Ester Del Duca, Bose Swaroop, Sacha Gnjatic, Gail Shattner, Joan Reibman, Nicholas A. Soter, Emma Guttman‐Yassky, Maria A. Curotto de Lafaille
Journal: Allergy (2022)

Abstract Background Atopic diseases are characterized by IgE antibody responses that are dependent on cognate CD4 T cell help and T cell‐produced IL‐4 and IL‐13. Current models of IgE cell differentiation point to the role of IgG memory B cells as precursors of pathogenic IgE plasma cells. The goal of this work was to identify intrinsic features of memory B cells that are associated with IgE production in atopic diseases. Methods Peripheral blood B lymphocytes were collected from individuals with physician diagnosed asthma or atopic dermatitis (AD) and from non‐atopic individuals. These samples were analyzed by spectral flow cytometry, single cell RNA sequencing (scRNAseq), and in vitro activation assays. Results We identified a novel population of IgG memory B cells characterized by the expression of IL‐4/IL‐13 regulated genes FCER2 / CD23 , IL4R , IL13RA1 , and IGHE , denoting a history of differentiation during type 2 immune responses. CD23 + IL4R + IgG + memory B cells had increased occurrence in individuals with atopic disease. Importantly, the frequency of CD23 + IL4R + IgG + memory B cells correlated with levels of circulating IgE. Consistently, in vitro stimulated B cells from atopic individuals generated more IgE + cells than B cells from non‐atopic subjects. Conclusions These findings suggest that CD23 + IL4R + IgG + memory B cells transcribing IGHE are potential precursors of IgE plasma cells and are linked to pathogenic IgE production.